10α-Hydroxy-β-isomorphine, a by-product of the synthesis of 10α-hydroxymorphine

Article abstract of DOI:10.1007/s00706-008-0077-3

A new compound was isolated from the reaction mixture after O-demethylation of 6-O-acetyl-10α-acetoxycodeine with boron tribromide. The structure of this compound, 10α-hydroxy-β-isomorphine, was elucidated by spectral data, and its spatial arrangement was

Full text of DOI:10.1007/s00706-008-0077-3

Monatsh Chem (2009) 140:485–487
DOI 10.1007/s00706-008-0077-3
ORIGINAL PAPER
10a-Hydroxy-b-isomorphine, a by-product of the synthesis
of 10a-hydroxymorphine
Bohumil Proksa Æ Richard Hercek Æ
´
´
Tibor Liptaj Æ Nada Pronayova
Received: 8 August 2008 / Accepted: 18 September 2008 / Published online: 25 October 2008
Ó Springer-Verlag 2008
Abstract A new compound was isolated from the reac-
tion mixture after O-demethylation of 6-O-acetyl-10a-
acetoxycodeine with boron tribromide. The structure of this
compound, 10a-hydroxy-b-isomorphine, was elucidated by
spectral data, and its spatial arrangement was deduced from
an NOE experiment. Capillary zone electrophoresis was
used for separation of morphine and its 10-hydroxy
analogues.
O-demethylation of this latter compound has been unsuc-
cessful. Spatial orientation of a new hydroxyl group in the
morphinane skeleton attached at C-10, i.e., trans versus the
C-9 nitrogen atom, has been deduced from the chemical
reactivity of derivatives [6].
We used codeine as a starting material for the synthesis
of 10a-hydroxymorphine, but besides the expected 10a-
hydroxymorphine, a new compound was isolated from the
reaction mixture. Identification of this new compound is
the subject of this paper.
Keywords Alkaloids ꢀ Structure elucidation ꢀ Isomers ꢀ
10a-Hydroxymorphine ꢀ Synthesis
Results and discussion
Introduction
Oxidation of codeine (1) with chromium(VI) oxide in
dilute sulfuric acid according to [4] afforded 10a-
hydroxycodeine (2), which was acetylated to the diacetate
3 and subsequently O-demethylated with boron tribromide.
Column chromatography of the concentrated extract of the
reaction mixture afforded 10a-hydroxymorphine (4) and a
new compound 5. Capillary zone electrophoresis was used
for analysis of all reaction mixtures and products and for
purification as well. Compounds 4 and 5 were well sepa-
rated by this method even in the plain electrolyte with
migration times tm = 4.239 and 4.380 min, with resolution
of peaks Rs = 3.25. Migration of these compounds was
reversed in the presence of hydroxypropyl-b-cyclodextrin
(tm = 4.887 and 4.717 min, respectively), which indicates
differences in the effective molecular volume of the sep-
arated compounds and their lipophilicity (Fig. 1).
10a-Hydroxymorphine is a pharmacopoeial impurity of
morphine, identified in stored dosage forms containing
morphine sulfate [1, 2]. Separation of this impurity from
the other oxidation products of morphine has been studied
by capillary zone electrophoresis in presence of cyclo-
dextrins [3].
10-Hydroxymorphine has been synthesized from 3-O-
allylmorphine by its oxidation with cold chromium(VI)
oxide acid in dilute sulfuric acid followed by deprotection
with sodium in liquid ammonia [4]; however, this synthesis
was not very efficient, and better results afforded oxidation
of codeine to 10a-hydroxycodeine [5]. On the other hand,
B. Proksa (&) ꢀ R. Hercek
The HR–MS spectrum of 5 disclosed an M ? 1 peak at
302.13846 corresponding to formula C17H20NO4, identical
with that of 4, but the NMR spectra (Tables 1, 2) of both
compounds were different, mainly in shifts of signals of
C-atoms of the ring. H–C correlation of signals of
Zentiva a.s., Nitrianska 100, 92027 Hlohovec, Slovakia
e-mail: bohumil.proksa@zentiva.sk
´
´
T. Liptaj ꢀ N. Pronayova
Faculty of Chemical and Food Technology,
Institute of Analytical Chemistry, Bratislava, Slovakia
123

486
B. Proksa et al.
2
R1O
Table 2 1H NMR chemical shifts (d/ppm) of compounds 4 and 5
(DMSO-d6; 25°C)
HO
O
1
3
4
A
11
R3
OH
Position
4
5
12
13
10
9
B
14
O
H
d/ppm
J/Hz
d/ppm
J/Hz
5
CH3
CH3
16
N
N
C 15
6
1
6.66 dd
6.52 d
4.63 d
4.06 dd
5.41 dd
5.38 d
3.13 d
4.59 d
2.42 s
8.1; 0.5
8.1
6.67 d
6.58 d
4.84 d
5.69 dd
5.86 dd
4.17 dd
3.13 s
8.4
R2O
8
OH
7
2
7.8
5
4.6
3.6
1
2
3
4
R1 = CH3 R2 = R3 = H
R1 = CH3 R2 = H R3 = OH
5
6
5.3; 2.4
10.2; 4.8
10.2
2.9
10.5; 3.0
10.2; 4.8
4.8; 4.8
–
7
R1 = CH3 R2 = COCH3 R3 = OCOCH3
R1 = R2 = H R3 = OH
8
9
10
4.9
4.52 d
2.31 dd
10.2
Fig. 1 Structure of prepared compounds
14
–
6.0; 1.8
compound 5 was performed according to results of a HSQC
experiment. A COSY experiment revealed inter alia
interaction of a proton attached to a carbon bearing a
hydroxyl group with H-7 and H-14, while H-5 interacted
with a proton attached to an sp2 carbon, which was not
observed in the spectrum of 10a-hydroxymorphine (4)
having the hydroxyl group attached at C-6. An HMBC
experiment with compound 5 disclosed 3J (2J) interactions
of a proton attached to a hydroxylated carbon with C-6 and
C-13, while H-5 interacted with C-4, C-6, C-7, C-12, and
C-15.
15a
15e
16a
16e
N–CH3
3-OH
6-OH
8-OH
10-OH
1.93 ddd 12.6; 12.5; 5.2 1.76 ddd 12.3; 12.3; 5.0
1.63 dd 12.6; 2.0 1.44 dd 12.3; 2.2
2.14 ddd 12.3; 12.2; 3.5 2.06 ddd 12.6; 12.3; 2.9
2.39 m
2.42 s
8.10 s
4.94 d
–
–
2.42 dd
2.42 s
9.00 s
–
12.6; 4.8
–
–
–
–
5.1
–
–
5.29 d
5.26 d
1.2
10.8
4.80 d
6.5
and 14 are situated on the same plane as rings C and D.
According to these data, compound 5 has a structure of (5a,
8a, 10a)-6,7-didehydro-4,5-epoxy-17-methyl-morphinan-
3,8,10-triol (10a-hydroxy-b-isomorphine) with absolute
configuration: (5S, 8R, 9S, 10S, 13S, 14R) (Fig. 2).
The ultimate evidence of the structure of compound 5
afforded an NOE experiment; irradiation of H-8 and H-14
resulted in the intensity enhancement of H-7, H-9, H-14,
and H-5, H-8, H-9, which confirmed that hydrogens 5, 8, 9,
Table 1 13C NMR chemical shifts (d/ppm) of compounds 4 and 5
(DMSO-d6; 25 °C)
Experimental
Position
4
5
d/ppm
d/ppm
Melting points: Kofler apparatus. NMR: Varian Unity-
Inova 600 MHz, 5-mm triple resonance PFG 1H sensitivity
optimized probe, 20 mg of sample in 0.6 cm3 DMSO-d6
(Merck, Darmstadt, Germany), 25 °C. All 2D correlation
experiments (COSY, HSQC, HMBC) were performed using
gradient-enhanced versions of pulse sequences to achieve
1
118.9
116.4
139.5
145.6
91.5
118.8
116.7
139.8
141.7
85.2
2
3
4
5
6
66.5
125.3
132.5
61.6
H
HO
7
131.4
129.5
67.5
1
8
H
9
67.5
OH
H
10
10
11
12
13
14
15
16
N–CH3
59.4
59.4
H
O
130.4
129.8
39.4
130.6
129.6
38.7
14
5
9
15
CH3
16
H
H
H
N
8
H
6
42.8
42.1
OH
7
H
35.3
36.6
H
46.5
46.5
43.6
42.9
Fig. 2 NOEs observed in spectrum of compound 5
123

10a-Hydroxy-b-isomorphine, a by-product of the synthesis of 10a-hydroxymorphine
487
clean spectra and good suppression of artifacts. In HSQC
and HMBC 180° adiabatic refocusing pulses were used.
NOE connectivity was determined using 1D NOESY
experiments. Selective excitation of the chosen protons was
based on double PFG spin-echo (DPFGSE) proposed by
Shaka et al. [7]. In DPFGSE selective 180° Gaussian pulses
were used to refocus magnetization of selected proton.
Their duration and amplitude were matched to the width of
the multiplet of the selected proton using the pulse pro-
gramming tool (Pbox) provided by the vendor of the
spectrometer. The typical setting was Gaussian with 20-Hz
effective bandwidth and corresponding duration of 45 ms.
Spectra were acquired with two mixing times: 0.5 and 1.0 s.
HR–MS: LTQ Orbitrap Hybrid (Thermo Scientific, Wal-
tham, USA), APCI ionization, positive mode, 400 °C ion
source temperature. IR: Model 983 spectrometer (Perkin
Elmer, Waltham, USA). Capillary electrophoresis: HP3DCE
(Agilent, Waldbronn, Germany), CC: Silica gel 60, 0.063–
0.200 mm, (Merck, Darmstadt, Germany), eluted with
methanol:ammonium hydroxide (99:1). TLC:DC Alufolien
Silica gel 60 F254, in methanol:ammonium hydroxide (99:1)
and chloroform:methanol:ammonium hydroxide (90:9:1),
UV detection at 254 nm. Elemental analyses: EA 1108
(Fisons, Winsford, UK) instrument with automatic data
evaluation EAGER 200; results agreed favorably with cal-
culated values.
cooled, concentrated in vacuum, the residue was dissolved
in cold water, and the pH was adjusted to 9 with aqueous
ammonia. The precipitate was filtered off, washed with
water, and dried at 40 °C. Yield was 2.0 g (79 %) of crude
diacetate 3. After recrystallization from ethanol, 1.6 g 3
(63%) were obtained as crystals. Mp 157–159 °C; MS: m/z
(%) = 399 (M?, 100), 357 (45), 315 (22).
Preparation of 10-hydroxy-b-isomorphine
(5, C17H19NO4)
Diacetate 3 (1.6 g, 4.0 mmol) dissolved in 40 cm3
dichloromethane was cooled to -5 °C, combined with
4 cm3 boron tribromide at 0–5 °C, and then the reaction
mixture was stirred for 4.5 h at ambient temperature. The
reaction mixture was cooled to 0 °C, and 100 cm3 water
was slowly added to the reaction mixture at a temperature
not exceeding 25 °C. Dichloromethane was distilled off
under vacuum, and the remaining mixture was heated to
90 °C for 1 h, activated charcoal was added, and the
mixture was filtered. The pH of the cooled filtrate was
adjusted to 8.5 with aqueous ammonia, and the mixture
was extracted with dichloromethane. The extract, con-
taining 44.2% of 4, and 52.6% of 5, was evaporated, and
the residue was chromatographed on silica with metha-
nol:ammonia (99:1) as eluent. Combined fractions with Rf
0.8 [methanol:ammonium hydroxide (99:1)] were evapo-
rated, and the residue was crystallized from methanol–
water to afford 0.6 g 5 (50.0%). Mp 235 °C (dec); 1H NMR
and 13C NMR data are given in Tables 1 and 2; IR (KBr):
m ¼ 3; 549 (O–H), 3,161; 2,933 (C–H); 1,644 (C=C); 1,616
(aromatic ring) cm-1; MS: m/z (%) = 301 (M?, 100); 286
(M–CH3, 1); 284 (M–OH, 28); 244 (6).
Analysis of reaction mixtures
A total of 0.5 cm3 of the reaction mixture was pipetted to a
10 cm3 volumetric flask, 2 cm3 of aqueous acetic acid (2%
v/v) was added, and the solution was made up to 10 cm3
with distilled water. This solution was filtered through a
membrane filter (0.20 lm), injected into the capillary
(150 mbar s), and analyzed under conditions: capillary: 40-
cm effective length, diameter 50 lm; electrolyte: 100 mM
TRIS, pH adjusted to 2.6 with phosphoric acid (8%, v/v);
30 kV; 25 °C; detector wavelength: 214 nm; data evalua-
tion: corrected area percent.
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92:485
Preparation of 10a-hydroxycodeine 6,10-diacetate
(3, C22H25NO6)
3. Proksa B (1999) J Pharm Biomed Anal 20:179
4. Rapoport H, Masamune H (1955) J Am Chem Soc 77:6359
5. Rapoport H, Stevenson GW (1954) J Am Chem Soc 76:1796
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10a-Hydroxycodeine [2, 2.0 g, 6.3 mmol, prepared
according to [5]], 5 cm3 acetanhydride, and 5 cm3 pyridine
were heated at 90 °C for 1 h. The reaction mixture was
123